Rett syndrome (RTT) is an X-linked neurodevelopmental disorder linked to motor system dysfunction as well as loss of communication skills and cognitive deficits. The mutation in the X-linked gene, encoding for methyl- CpG binding protein 2 (MeCP2), accounts for over 80% of RTT cases. Mutant MeCP2 mice exhibit phenotypic characteristics similar to those in RTT patients, i.e. impairment of synaptic function and plasticity. Recent data generated in our laboratory demonstrate that T cells can regulate synaptogenesis mediated through control of astrocyte function. Depletion of T cells correlates with reduced synaptogenesis and impaired cognition, whereas boost of immune responses following vaccination with a synthetic copolymer (Cop-1) improves cognitive performance. Our major hypothesis is that the malfunctioning immune system in RTT patients and MeCP2tmHzo/MeCP2+ mice contributes to disease pathogenesis and that a boost in immune response may impede disease progression. First, we aim to characterize the adaptive and innate immune function in MeCP2tmHzo/MeCP2+ mice. We will assess the immune system during disease development by addressing the function of innate and adaptive immunity. Our second aim addresses the role of immunity in RTT onset and progression. We expect that depletion of T cells from MeCP2tmHzo/MeCP2+ mice will exacerbate disease, whereas exchange or boost of the existing immune system will ameliorate disease symptoms and increase longevity. Mice will be analyzed based on neuroanatomical examinations of synaptic puncta, cognitive performance, and life span as well as observations of motor and social behavior. PUBLIC HEALTH RELEVANCE: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder linked to motor system dysfunction as well as loss of communication skills and cognitive deficits. Recent data generated in our laboratory demonstrate that T cells can regulate synaptic plasticity and cognition. In this proposal we will develop our hypothesis that the malfunctioning immune system in RTT patients and MeCP2tmHzo/MeCP2+ mice contributes to disease pathogenesis and thus boost of immune response using vaccine approach may slow down disease progression.